Few medical countermeasures are currently available to treat chronic multi-organ failures following exposure to life-threatening radiation during radiation emergencies and nuclear disasters, especially for aged victims. Endogenous adult stem cells (ASCs), also called tissue-specific stem cells, exist, often in a scarce quantity, in almost every adult tissues and organs. However, how to robustly induce ASCs by administering soluble molecules to repair the injured organs, which could be more clinically applicable and cost-effective, remains largely unknown. We found that systemic administration of recombinant Fc chimeras of human R-spondin 1 and Slit2 (rRspo1-Fc/rSlit2-Fc) protected young mice from death, even when given 24 hours after lethal doses of whole body irradiation (WBI). Mechanistically, WBI induced the expression of Robo1 in intestinal stem cells (ISCs) and hematopoietic stem cells (HSCs). Rspo1 acted synergistically with Slit2 to enhance the survival of irradiated ISCs and HSCs and to accelerate the repair of radiation-induced acute gut and bone marrow injuries. In this proposal, we will test (1) the efficacy of rRspo1-Fc/rSlit2-Fc in mitigation of chronic radiation syndrome in young and older male and female mice, and (2) the long-term effects of rRspo1-Fc/rSlit2-Fc in irradiated young and older male and female mice. We believe that the regimen of rRspo1-Fc/rSlit2-Fc may provide a safe and effective pharmacological method to stimulate the repair of radiation-mediated chronic damage of essential tissues in aged victims.